Is EGFR p.Leu833Phe (c.2499G>T) pathogenic?

EGFR p.Leu833Phe (c.2499G>T) is classified Likely pathogenic in EGFR (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9723); Absent from gnomAD v4.1; Associated with lung adenocarcinoma.

What condition is associated with EGFR p.Leu833Phe (c.2499G>T)?

EGFR p.Leu833Phe (c.2499G>T) is associated with lung adenocarcinoma (ClinVar).

How common is EGFR p.Leu833Phe (c.2499G>T) in the general population?

EGFR p.Leu833Phe (c.2499G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Leu833Phe (c.2499G>T)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

EGFR p.Leu833Phe

c.2499G>T · rs2128964427 · VCV2583129

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lung adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic ✓ concordant with ClinVar
REVEL	0.37	indeterminate
SaProt	LLR -2.67	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.12, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EGFR
Protein: p.Leu833Phe
Coding: c.2499G>T
MANE Select: NM_005228
dbSNP: rs2128964427
Type: single nucleotide variant
Location: chr7:55191748 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 833: a UniProt-annotated variant site (found in a lung cancer sample; more sensitive to gefitinib than wild-type); the protein kinase domain

Full EGFR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lung adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGFR p.Leu833Val Conflicting classifications of pathogenicity ⚠ same residue
EGFR p.Arg776Cys Uncertain significance ★★ ⚠ same condition
EGFR p.Glu554Gly Uncertain significance ★★ ⚠ same condition
EGFR c.88+24313G>C Uncertain significance ★ same condition
EGFR p.Arg831His Conflicting classifications of pathogenicity ★ ⚠ same condition
EGFR p.Glu330Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
EGFR p.Glu709Ala Uncertain significance ★ ⚠ same condition
EGFR p.Leu833Pro Uncertain significance ★ same residue

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/egfr-p-leu833phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown